Withania somnifera Reverses Transactive Response DNA Binding Protein 43 Proteinopathy in a Mouse Model of Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration

• DOI: 10.1007/s13311-016-0499-2
• Publication Date: 2016-12-07T15:28:45Z
• Authors: Kallol Dutta; Priyanka Patel; Reza Rahimian; Daniel Phaneuf; Jean-Pierre Julien
• Keywords: Frontotemporal lobar degeneration; Rotarod performance test

Abnormal cytoplasmic mislocalization of transactive response DNA binding protein 43 (TARDBP or TDP-43) in degenerating neurons is a hallmark amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Our previous work suggested that nuclear factor kappa B (NF-κB) may constitute therapeutic target for TDP-43-mediated disease. Here, we investigated the effects root extract Withania somnifera (Ashwagandha), an herbal medicine anti-inflammatory properties, transgenic mice expressing genomic fragment encoding human TDP-43A315T mutant. Ashwagandha was administered orally to hTDP-43A315T period 8 weeks starting at 64 48 age males females, respectively. The treatment ameliorated their motor performance on rotarod test cognitive function assessed by passive avoidance test. Microscopy examination tissue samples revealed improved innervation neuromuscular junctions, attenuated neuroinflammation, reduced NF-κB activation. Remarkably, reversed hTDP-43 spinal brain cortical it aggregation. In vitro evidence presented neuronal rescue TDP-43 be due indirect effect factors released from microglial cells exposed Ashwagandha. These results suggest its constituents might represent promising therapeutics proteinopathies.